Article
Chemistry, Medicinal
Yang Zheng, Magali van den Kerkhof, Tiffany van der Meer, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Iwan J. P. de Esch, Marco Siderius, An Matheeussen, Louis Maes, Geert Jan Sterk, Guy Caljon, Rob Leurs
Summary: The discovery of 5-phenylpyrazolopyrimidinone analogs as a novel series of antitrypanosomal agents shows promise for developing new medications to treat Human African Trypanosomiasis (HAT). The most potent compound, 30, has a low toxicity potential and exhibits high in vitro and in vivo antitrypanosomal activity against T. b. brucei.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Laura A. T. Cleghorn, Richard J. Wall, Seibastien Albrecht, Stuart A. MacGowan, Suzanne Norval, Manu De Rycker, Andrew Woodland, Daniel Spinks, Stephen Thompson, Stephen Patterson, Victoriano Corpas Lopez, Gourav Dey, Iain T. Collie, Irene Hallyburton, Robert Kime, Frederick R. C. Simeons, Laste Stojanovski, Julie A. Frearson, Paul G. Wyatt, Kevin D. Read, Ian H. Gilbert, Susan Wyllie
Summary: Despite advancements in treatment options, there is a need for new drugs to eradicate human African trypanosomiasis (HAT). In this study, potent 2,4-diaminothiazoles were developed as drug-like inhibitors against Trypanosoma brucei. Animal testing confirmed the efficacy in the hemolymphatic stage, but optimization for brain penetration did not achieve the desired in vivo efficacy due to a shift in mechanism of action. Subsequent studies identified a nonessential kinase as the target and emphasized the importance of cytotoxic drugs for HAT treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jens C. Lindhof, Irina Ihnatenko, Marco J. Mueller, Oliver C. F. Orban, Cecilia Ortiz, Diego Benitez, Estefania Dibello, Leonardo L. Seidl, Marcelo A. Comini, Conrad Kunick
Summary: Parasitic kinetoplastid diseases pose serious threats to populations in the (sub-)tropics. Current drugs lack proper properties, requiring the urgent need for new candidates. Through molecular simplification and ring disconnection approaches, we identified new compounds with improved potency and selectivity against the target enzyme.
Article
Chemistry, Medicinal
William J. Robinson, Annie E. Taylor, Solange Lauga-Cami, George W. Weaver, Randolph Rj Arroo, Marcel Kaiser, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Kuldip Singh, Tanja Schirmeister, Adolfo Botana, Chatchakorn Eurtivong, Avninder S. Bhambra
Summary: Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, with current therapy limitations and the need for further investigation. Novel anti-trypanosomal compounds show promising potential, providing scaffolds for future drug development targeting the disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Melissa L. Sykes, Emily K. Kennedy, Kevin D. Read, Marcel Kaiser, Vicky M. Avery
Summary: Chagas disease and Human African Trypanosomiasis (HAT) are parasitic diseases that pose a serious threat to human health. The existing treatment methods are not highly effective, thus there is a need for new therapeutic drugs. Through in vitro assays, compounds with selective activity against these parasites have been identified and evaluated for further research and development.
Article
Multidisciplinary Sciences
Mouhamadou M. Dieng, Kiswend-sida M. Dera, Percy Moyaba, Gisele M. S. Ouedraogo, Guler Demirbas-Uzel, Fabian Gstottenmayer, Fernando C. Mulandane, Luis Neves, Sihle Mdluli, Jean-Baptiste Rayaisse, Adrien M. G. Belem, Soumaila Pagabeleguem, Chantel J. de Beer, Andrew G. Parker, Jan Van den Abbeele, Robert L. Mach, Marc J. B. Vreysen, Adly M. M. Abd-Alla
Summary: The sterile insect technique is an effective and sustainable method for managing insect pests. This study examines the interaction between Sodalis bacteria and Trypanosoma infection in tsetse flies. The presence of Sodalis and Trypanosoma varied among different countries and tsetse species. The study also found differences in the prevalence of specific Trypanosoma species in different regions.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Medicinal
Diego Benitez, Estefania Dibello, Mariana Bonilla, Marcelo A. Comini
Summary: African trypanosomiasis is a major health problem in endemic countries and requires new drugs for treatment. In this study, a simple and economical high-throughput screening assay was developed using a bioluminescent cell line of the trypanosome parasite. The assay showed high sensitivity and accuracy in identifying compounds with potent anti-parasitic activity.
DRUG DEVELOPMENT RESEARCH
(2022)
Review
Endocrinology & Metabolism
Fanta Fall, Lucia Mamede, Laura Schioppa, Allison Ledoux, Pascal De Tullio, Paul Michels, Michel Frederich, Joelle Quetin-Leclercq
Summary: Background: Trypanosoma brucei is the causative agent of sleeping sickness, a disease that can cause serious neurological disorders and is fatal if not treated. Traditional treatments have limitations such as toxicity and resistance, so metabolomics is being used to better understand the parasite's metabolism and find new treatment targets. This review aims to comprehensively describe the biology of T. brucei and identify targets for new drugs through metabolomics.
Article
Chemistry, Medicinal
Huji Turdi, Hannguang Chao, Jon J. Hangeland, Saleem Ahmad, Wei Meng, Robert Brigance, Guohua Zhao, Wei Wang, Fang Moore, Xiang-Yang Ye, Arvind Mathur, Xiaoping Hou, James Kempson, Dauh-Rurng Wu, Yi-Xin Li, Anthony Azzara, Zhengping Ma, Ching-Hsuen Chu, Luping Chen, Mary Jane Cullen, Suzanne Rooney, Susan Harvey, Lisa Kopcho, Reshma Panemangelor, Lynn Abell, Kevin O'Malley, William J. Keim, Elizabeth Dierks, Shu Chang, Kimberly Foster, Atsu Apedo, David Harden, Marta Dabros, Qi Gao, Mary Ann Pelleymounter, Jean M. Whaley, Jeffrey A. Robl, Dong Cheng, R. Michael Lawrence, Pratik Devasthale
Summary: Inhibition of MGAT2 is a potential therapeutic approach for metabolic disorders. A high-throughput screening identified the aryl dihydropyridinone compound 1 as a hit, leading to the development of stable and selective MGAT2 inhibitors. Among them, compound 21s was selected as a clinical candidate based on its efficacy in inducing weight loss and acceptable safety profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemical Research Methods
Saman Honarnejad, Stan van Boeckel, Helma van den Hurk, Steven van Helden
Summary: The European Lead Factory (ELF) consortium offers European academics and small to medium enterprises access to over 500,000 unique compounds, an advanced screening platform, and expertise in early drug discovery. Through optimizing 76 primary assays in projects targeting eight target classes across seven therapeutic areas, ELF has demonstrated the potential for centralized high-throughput screening.
Article
Chemistry, Medicinal
Sangmi Oh, M. Daben J. Libardo, Shaik Azeeza, Gary T. Pauly, Jose Santinni O. Roma, Andaleeb Sajid, Yoshitaka Tateishi, Caroline Duncombe, Michael Goodwin, Thomas R. Ioerger, Paul G. Wyatt, Peter C. Ray, David W. Gray, Helena I. M. Boshoff, Clifton E. Barry
Summary: Pyrazolo[1,5-a]pyrimidin-7(4H)-one was identified as a potential antituberculosis lead through high-throughput whole-cell screening. The synthesized analogues showed substantial improvements in antitubercular activity with low cytotoxicity, and promising activity against Mtb. Resistance to these compounds was found to be due to mutation of a specific hydroxylase.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Michael Thomas, Stephen Brand, Manu De Rycker, Fabio Zuccotto, Iva Lukac, Peter G. Dodd, Eun-Jung Ko, Sujatha Manthri, Kate McGonagle, Maria Osuna-Cabello, Jennifer Riley, Caterina Pont, Frederick Simeons, Laste Stojanovski, John Thomas, Stephen Thompson, Elisabet Viayna, Jose M. Fiandor, Julio Martin, Paul G. Wyatt, Timothy J. Miles, Kevin D. Read, Maria Marco, Ian H. Gilbert
Summary: An urgent need for new treatments for visceral leishmaniasis prompted the discovery of a preclinical candidate, GSK3494245/DDD01305143, through a medicinal chemistry program. The compound, identified through extensive scaffold-hopping exercise, showed in vivo efficacy as a proteasome inhibitor, shedding light on structure-activity relationships in the series.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Immunology
Felix Calderon, Alan H. Fairlamb, Mike Strange, Pauline Williams, Carl F. Nathan
Summary: The unique experiment of bringing academic and industrial scientists together to tackle infectious diseases has been successful. The Tres Cantos Open Lab Foundation has sustained progress in addressing tuberculosis, protozoal infections, and enteric bacterial diseases through extended stays of academics at a pharmaceutical company. This model, guided by independent experts, complements other public-private partnerships with similar goals.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Lee A. Armstrong, Sven M. Lange, Virginia Dee Cesare, Stephen P. Matthews, Raja Sekhar Nirujogi, Isobel Cole, Anthony Hope, Fraser Cunningham, Rachel Toth, Rukmini Mukherjee, Denisa Bojkova, Franz Gruber, David Gray, Paul G. Wyatt, Jindrich Cinatl, Ivan Dikic, Paul Davies, Yogesh Kulathu
Summary: Among the 16 non-structural proteins encoded by SARS CoV-2, Nsp3 is the largest and plays important roles in the viral life cycle. The papain-like protease domain (PLpro) encoded within Nsp3 cleaves viral polypeptide, as well as ubiquitin and ISG15 from host cell proteins. Screening clinical compounds, five were found to inhibit PLpro but showed no significant antiviral activity in cellular SARS-CoV-2 infection assays, highlighting the importance of alternative methods like engineered nanobodies to block PLpro activity.
Article
Infectious Diseases
Nina Svensen, Susan Wyllie, David W. Gray, Manu De Rycker
Summary: Chagas disease, caused by Trypanosoma cruzi, is a highly neglected tropical disease with inadequate current treatments; recent failures in clinical trials have led to the development of new model systems to better understand the reasons for these failures. A new live-imaging RoK assay has been introduced for T. cruzi, offering high reproducibility and high time-resolution data for clinical compounds and new entities, allowing for prioritization of fast-acting compounds and tracking of individual parasites' fate, among other benefits.
PLOS NEGLECTED TROPICAL DISEASES
(2021)
Article
Chemistry, Medicinal
Kate McGonagle, Gary J. Tarver, Juan Cantizani, Ignacio Cotillo, Peter G. Dodd, Liam Ferguson, Ian H. Gilbert, Maria Marco, Tim Miles, Claire Naylor, Maria Osuna-Cabello, Christy Paterson, Kevin D. Read, Erika G. Pinto, Jennifer Riley, Paul Scullion, Yoko Shishikura, Frederick Simeons, Laste Stojanovski, Nina Svensen, John Thomas, Paul G. Wyatt, Pilar Manzano, Manu De Rycker, Michael G. Thomas
Summary: This study describes a series of disubstituted piperazines with good potency against Trypanosoma cruzi, but poor metabolic stability. Strategies such as lowering logD, bioisosteric replacements, and plate-based arrays are used to address this issue. The challenges of improving pharmacokinetic profile while maintaining potency are discussed.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Chemistry, Medicinal
Laura A. T. Cleghorn, Richard J. Wall, Seibastien Albrecht, Stuart A. MacGowan, Suzanne Norval, Manu De Rycker, Andrew Woodland, Daniel Spinks, Stephen Thompson, Stephen Patterson, Victoriano Corpas Lopez, Gourav Dey, Iain T. Collie, Irene Hallyburton, Robert Kime, Frederick R. C. Simeons, Laste Stojanovski, Julie A. Frearson, Paul G. Wyatt, Kevin D. Read, Ian H. Gilbert, Susan Wyllie
Summary: Despite advancements in treatment options, there is a need for new drugs to eradicate human African trypanosomiasis (HAT). In this study, potent 2,4-diaminothiazoles were developed as drug-like inhibitors against Trypanosoma brucei. Animal testing confirmed the efficacy in the hemolymphatic stage, but optimization for brain penetration did not achieve the desired in vivo efficacy due to a shift in mechanism of action. Subsequent studies identified a nonessential kinase as the target and emphasized the importance of cytotoxic drugs for HAT treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Ian H. Gilbert, James S. Martin, Claire J. Mackenzie, De Lin, Nadine Homeyer, David W. Gray, Fabio Zuccotto
Summary: There is a urgent need to develop new therapeutics with novel modes of action to target Gram-negative bacterial infections. Previous research identified FabA as a potential drug target in Pseudomonas aeruginosa, a significant clinical concern. This paper describes the preparation of analogues to inhibit FabA, but unfortunately, the analogues did not increase inhibition due to enzyme occlusion.
Article
Biology
Marie Miglianico, Judith M. Bolscher, Martijn W. Vos, Karin J. M. Koolen, Marloes de Bruijni, Deeya S. Rajagopal, Emily Chen, Michael Kiczun, David Gray, Brice Campo, Robert W. Sauerwein, Koen J. Dechering
Summary: This study reveals that chemical intervention against malaria parasites mostly occurs during the liver schizogony stage, with limited effects on sporozoite viability and motility. However, ten compounds showed significant impact on liver schizont development.
COMMUNICATIONS BIOLOGY
(2023)
Article
Chemistry, Medicinal
Michael G. Thomas, Kate McGonagle, Paul Rowland, David A. Robinson, Peter G. Dodd, Isabel Camino-Diaz, Lorna Campbell, Juan Cantizani, Pablo Castaneda, Daniel Conn, Peter D. Craggs, Darren Edwards, Liam Ferguson, Andrew Fosberry, Laura Frame, Panchali Goswami, Xiao Hu, Justyna Korczynska, Lorna MacLean, Julio Martin, Nicole Mutter, Maria Osuna-Cabello, Christy Paterson, Imanol Pena, Erika G. Pinto, Caterina Pont, Jennifer Riley, Yoko Shishikura, Frederick R. C. Simeons, Laste Stojanovski, John Thomas, Karolina Wrobel, Robert J. Young, Filip Zmuda, Fabio Zuccotto, Kevin D. Read, Ian H. Gilbert, Maria Marco, Timothy J. Miles, Pilar Manzano, Manu De Rycker
Summary: There is an urgent need for new treatments for Chagas disease. The discovery of a preclinical candidate for visceral leishmaniasis prompted the investigation of alternative proteasome inhibitors for Trypanosoma cruzi, the parasite causing Chagas disease. A selective pyridazinone compound was identified and optimized for efficacy studies, showing potential as a new treatment for Chagas disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Correction
Multidisciplinary Sciences
Susan Wyllie, Michael Thomas, Stephen Patterson, Sabrinia Crouch, Manu De Rycker, Rhiannon Lowe, Stephanie Gresham, Michael D. Urbaniak, Thomas D. Otto, Laste Stojanovski, Frederick R. C. Simeons, Sujatha Manthri, Lorna M. MacLean, Fabio Zuccotto, Nadine Homeyer, Hannah Pflaumer, Markus Boesche, Lalitha Sastry, Paul Connolly, Sebastian Albrecht, Matt Berriman, Gerard Drewes, David W. Gray, Sonja Ghidelli-Disse, Susan Dixon, Jose M. Fiandor, Paul G. Wyatt, Michael A. J. Ferguson, Alan H. Fairlamb, Timothy J. Miles, Kevin D. Read, Ian H. Gilbert
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)